Pharmacokinetics of (R)- and (S)-cyclophosphamide and their dechloroethylated metabolites in cancer patients

The complete pharmacokinetics (PK) of (R)- and (S)-cyclophosphamide (CP) an d their dechloroethylated (DCE) metabolites have not been reported to date. We collected plasma and urine samples from 12 cancer patients and determin ed concentrations of both enantiomers of CP and DCE-CP using a chiral GC-MS method. AU concentrations of (R)-CP, (S)-CP, (R)-DCE-CP, and (S)-DCE-CP we re simultaneously modeled using an enantiospecific compartmental PK model. A population PK analysis was performed. Enantiospecific differences between (R)- and (S)-CP were found for the formation clearance of CP to the DCE me tabolites (Cl-f: 0.25 (R) vs. 0.14 (S) L/h). No difference was found betwee n enantiomers for Cl-40H, Cld, Cl(m)(R), Cl-T, or T-1/2. In contrast to the adolescent and adult group of patients, a child (6 years old) appeared to have a very different PK and metabolic profile (Bayesian control analysis). Proportions of the (R,S)-CP doses transformed to the (R)-DCE- and (S)-DCE- CP were much higher (R:25 vs. 1.9%, and S: 38 vs. 3.6%), while formation of active metabolites was much lower (R: 42 vs. 74%, and S: 48 vs. 77%). CP a ppears to be enantioselectively metabolized to the DCE metabolites. This PK model can evaluate the proportion of a CP dose that is transformed to toxi c or active metabolites. It may therefore be used to optimize CP treatment, to identify important drug interactions and/or patients with an abnormal m etabolic profile. Chirality 11.301-308, 1999, (C) 1999 Wiley-Liss, Inc.